1. Field of the Invention
This invention relates to analogs of glycyl-L-prolyl-L-glutamic acid (GPE). In particular, this invention relates to neuroprotective GPE analogs, to methods of making them, to pharmaceutical compositions containing them, and to their use in treating neurological disorders resulting from brain injury and characterized by non-convulsive brain seizures.
2. Description of Related Art
Each year approximately 1.5 million people in the U.S.A. sustain a traumatic brain injury with an estimated 1.0 million hospitalised. Of these, 225,000 are moderate to very severe and 50,000 result in death. These injuries can be caused by concussions, penetrating injury, contusions and diffuse axonal injury resulting from tearing of brain tissue. Traumatic brain injury is a difficult and often frustrating condition to treat. Blunt head trauma can result in brain hemorrhage, swelling and increased intracranial pressure. Penetrating wounds caused by projectiles can be particularly difficult because of the rapid absorption by brain tissues of a large amount of kinetic energy and the high degree of damage that can result. As a direct result of such injuries, brain cells can be damaged or die. Additionally, secondary effects can further exacerbate the loss of functional neurons. For example, cellular damage can release cytokines and other chemoattractive molecules into the brain and can cause inflammation. Inflammation itself can cause additional damage to brain tissues and cells through the release of proteases and other inflammatory mediators, which may recruit yet additional cell types and exacerbate the problems further.
Many attempts are made to reduce the severity of brain injury. Surgery can be used to remove projectiles, bone fragments or other debris from the brain. Additionally, surgery can be successful in certain cases to relieve increased intracranial pressure, which can cause additional nerve damage, either through a direct effect on pressure, or an effect related to changes in blood flow to affected portions of the brain. For example, a focal traumatic injury that causes bleeding or increased vascular permeability can produce an area of increased hydrostatic pressure. If the pressure is sufficiently high, blood flow to nearby portions of uninjured neural tissue can be reduced, compromising oxygenation of the affected tissue. Further, decreased blood flow, if severe enough, can cause starvation of brain tissues due to decreased flow of nutrients to the affected areas. As a result of these changes, in most patients with traumatic brain injury, recovery is often slow and incomplete. With prolonged periods of injury, neurological functions can be severely compromised and neural deficits may persist for many years, or even for the remainder of the patient's lifetime.
In addition to traumatic brain injury, stroke or severe hypoxia/ischemia can also result in brain injury. In many cases, patients with stroke exhibit similar signs and symptoms as patients with traumatic brain injury, including penetrating ballistic brain injury (PBBI). Further, perinatal asphyxia and coronary artery bypass graft (CABG) surgery, brain seizures and neurotoxic agents can lead to brain injury.
In many types of brain injury, neural deficits and neurological signs may be easy to evaluate. In some cases, impairment of motor function or abnormalities in electroencephalographic (EEG) signals is observed. In many animals and humans with traumatic brain injury, stroke or severe hypoxia/ischemia, a type of delayed EEG abnormality or brain seizure may evolve that is associated with overt motor convulsions and is therefore clearly identifiable by observers of such patients and thereby treatable with established anti-epileptic drug (AED) therapy.
However, in most cases of brain injury acute/early monitoring of EEG brain function is impossible or impractical. Here seizures may occur that are not associated with overt motor abnormalities. Without continuous EEG monitoring these “non-convulsive seizures” (“NCS”) or “silent brain seizures” (“SBS”) are not observed as a clinical feature of the brain trauma and go untreated. Nonetheless, such non-convulsive seizures can reflect severe brain injury. In one study, a subgroup of patients with severe traumatic brain injury experienced electroencephalographic signs of seizures, but had no convulsions (Vespa et al., J. Neurosurg 91:750-760 (1999), expressly incorporated herein fully by reference.
Non-convlusive seizures are not only symptomatic, but also can contribute to poor patient outcome. Thus, it is desirable to identify useful treatments for NCS. Although gabapentin and ethosuximide have been reported to reduce experimental NCS, many conventional antiepileptic agents are ineffective (Williams et al., J. Pharmacol. Exp. Therap. 311:220-227 (2004), expressly incorporated herein fully by reference). Furthermore, efforts to treat NCS in human TBI with standard AED therapies have proven ineffective thereby identifying a critical care need in the art for improved methods of treating NCS.
It had been previously believed that mature nervous tissue is incapable of regeneration or recovery after severe injuries. Thus, few attempts have been made to treat brain damage to restore neural function. Fortunately, this misapprehension is being reversed, due in large part to recent studies on neural regeneration. For example, insulin-like growth factor 1 (IGF-1) has been shown to promote neural survival in animals with brain injuries. The N-terminal tripeptide of IGF-1, glycyl-prolyl-glutamate (Gly-Pro-Glu; GPE or Glypromate™) has similar neuroprotective effects. In fact, GPE has been used both in vitro and in vivo to treat neurodegeneration. However GPE is rapidly hydrolyzed by enzymes in plasma and in tissues thereby contributing to a relatively short half-life in vivo. Therefore, there is a great need for new types of therapies that can be used to treat neural damage associated with brain injuries resulting from stroke, various traumatic brain insults, coronary artery by-pass graft, hypoxic-ischemic episodes, etc.
EP 0 366 638 discloses GPE (a tri-peptide consisting of the amino acids Gly-Pro-Glu) and its di-peptide derivatives Gly-Pro and Pro-Glu. EP 0 366 638 discloses that GPE is effective as a neuromodulator and is able to affect the electrical properties of neurons.
WO95/172904 discloses that GPE has neuroprotective properties and that administration of GPE can reduce damage to the central nervous system (CNS) by the prevention or inhibition of neuronal and glial cell death.
WO 98/14202 discloses that administration of GPE can increase the effective amount of choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD), and nitric oxide synthase (NOS) in the central nervous system (CNS).
WO99/65509 discloses that increasing the effective amount of GPE in the CNS, such as by administration of GPE, can increase the effective amount of tyrosine hydroxylase (TH) in the CNS in order to increase TH-mediated dopamine production in the treatment of diseases such as Parkinson's disease.
WO02/16408 discloses GPE analogs capable of inducing a physiological effect equivalent to GPE within a patient. The applications of the GPE analogs include the treatment of acute brain injury and neurodegenerative diseases, including but not limited to, injury or disease in the CNS.
The disclosures of these and other documents referred to in this application (including in the Figures) are expressly incorporated herein by reference as if each one was individually incorporated by reference.